title: Potent antitumor activity of the novel HSP90 inhibitors AUY922 and HSP990 in neuroendocrine carcinoid cells.
abstract: The heat shock protein (HSP) 90 chaperone machine involved in numerous oncogenic signaling pathways is overexpressed in cancer cells and is currently being evaluated for anticancer therapy. Neuroendocrine tumors (NETs) of the gastroenteropancreatic (GEP) system comprise a heterogeneous group of tumors with increasing incidence and poor prognosis. Here, we report the antiproliferative effects of the HSP90 inhibitors AUY922 and HSP990 in neuroendocrine tumor cells. Treatment of human pancreatic BON1, bronchopulmonary NCI-H727 and midgut carcinoid GOT1 neuroendocrine tumor cells with increasing concentrations of AUY922 and HSP990 dose-dependently suppressed cell viability. Significant effects on neuroendocrine cell viability were observed with inhibitor concentrations as low as 5 nM. Inhibition of cell viability was associated with the induction of apoptosis as demonstrated by an increase in sub-G1 events and PARP cleavage. HSP90 inhibition was associated with decreased neuroendocrine ErbB and IGF-I receptor expression, decreased Erk and Akt phospho-rylation and the induction of HSP70 expression. These findings provide evidence that targeted inhibition of upregulated HSP90 activity could be useful for the treatment of aggressive neuroendocrine tumors resistant to conventional therapy.
authors.affiliation: Department of Internal Medicine II Campus Grosshadern, University-Hospital, Ludwig-Maximilians-University of Munich, D‑81377 Munich, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Zitzmann
authors.forename: Galina
authors.initials: G
authors.lastname: Ailer
authors.forename: George
authors.initials: G
authors.lastname: Vlotides
authors.forename: Gerald
authors.initials: G
authors.lastname: Spoettl
authors.forename: Julian
authors.initials: J
authors.lastname: Maurer
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Auernhammer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002276:Carcinoid Tumor / Q000188:drug therapy*; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy* / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis; D012118:Resorcinols / Q000494:pharmacology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D010750:Phosphoproteins; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D011728:Pyridones; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D012118:Resorcinols; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C570862:2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido(4,3-d)pyrimidin-5(6H)-one; C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; C087000:EIF4EBP1 protein, human; C508053:ERBB2 protein, human